The rising cost of healthcare, driven by ageing populations and chronic disease prevalence, places mounting pressure on health systems. This trend risks prioritizing cost-efficiency over clinical value. In response, healthcare models are evolving toward value-based care, outcome-driven reimbursement, hospital-at-home frameworks, and data-informed prevention strategiesâ all aiming to optimize resources and improve patient outcomes. In this context, wearable biosensors emerge as key enablers. By enabling continuous, remote biomarker monitoring, they support early diagnosis, patient stratification, and decentralized care. They also generate large-scale real-world data to evaluate treatment efficacy and inform data-driven medicine. Beyond clinical utility, wearable biosensors contribute to digital health innovation, including biomarker discovery, personalized therapies, and novel paradigms such as digital twins and in silico trials. Combined with AI, they support predictive, preventive, and personalized care. Among the various fluids accessible for sensing, dermal interstitial fluid (dISF)â the liquid surrounding tissue cellsâ stands out as a promising yet underexplored matrix for minimally invasive biomarker monitoring. This thesis aims to lay the foundations for robust, low-power, multimodal wearable sensors for quasi-continuous monitoring in dISF. The main focus is the development of a biosensor for C-reactive protein (CRP), a key inflammatory marker, with pH sensing also explored to demonstrate platform versatility. We first addressed biomarker availability in dISF via five clinical studies using a custom microneedle-based collector. Profiling over 50 biomarkers revealed that although total protein content in dISF is 50â 60% lower than in serum, relative protein composition remains consistent. Several cytokines correlated well with serum levels, while others showed dISF-specific enrichment or depletion. Dynamic monitoring confirmed CRP increases post-COVID-19 vaccination, diurnal cortisol variation, and lactate elevation during exercise. Building on these findings, we developed a highly specific and sensitive CRP assay using surface plasmon resonance (SPR) as a benchmark. A monoclonal Fab fragment (Fab CRP) achieved robust detection across physiological and pathological ranges in both buffer and dISF-like media. For miniaturization, we evaluated electrochemical transduction methods. Fab CRP immobilization was confirmed on various substrates via Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). We demonstrated CRP detection using silicon nanowire and graphene field-effect transistors (FETs) in low-ionic-strength media. However, performance was inhibited in physiological buffer due to Debye screening, prompting a shift to AC-based sensing. In parallel, we introduced a constant-current method for pH sensing using silicon nanowire ISFETs, achieving <1% error compared to lab benchmarks. We then implemented an AC-based biosensing platform using a lock-in amplifier and a simplified two-electrode setup. This system enabled specific, dose-dependent CRP detection in dISF-like and physiological buffers, with a detection limit of 0.08⠯Όg/mL and log-linear response matching SPR. These results establish dISF as a clinically relevant fluid for wearable biosensing and support the integration of CRP, pH, and additional biomarkers into microneedle platforms.